The Yale Specialized Center of Research in Hypertension focuses on identification of the inherited abnormalities that contribute to high blood pressure and its consequences. To date, we have identified mutations in 4 genes that raise blood pressure, 8 genes that lower blood pressure, linkage for two more Mendelian hypertensive disease, and linkage for blood pressure in the general population. These findings have demonstrated the key role of renal salt homeostasis in determination of blood pressure variation in humans, and have begun to identify molecular mechanisms underlying relationships between blood pressure and bone density. In the current proposal, we propose a series of investigations that will extend these studies. Taking genes in which we have shown mutations alter blood pressure, we examine the impact of variants in these genes on blood pressure and related phenotypes in the Framingham Heart Study. We also search for a gene accounting for a substantial fraction of blood pressure variance in this population, and search for genes contributing to a common complication of hypertension, end stage renal disease. We continue our identification of Mendelian traits that affect blood pressure, and pursue the clinical consequences of these mutations. Finally, since virtually all known causes of hypertension act via a common pathway of increased activity of the amiloride-sensitive epithelial sodium channel, we investigate the signaling pathway that regulates the activity of this channel. These studies will continue to provide key information regarding the causes and consequences of hypertension in humans that have clinical and therapeutic implications.